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THE PRURITUS OF CHOLESTASIS
PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING CHOLANGITIS, AND ADULT CHOLANGIOPATHIES
1089-3261/98 $8.00
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THE PRURITUS OF CHOLESTASIS Evolving Pathogenic Concepts Suggest New Therapeutic Options Nora V. Bergasa, MD, and E. Anthony Jones, MD
"Like lying on a bed of cactus" is how one patient with the pruritus of cholestasis described her This form of pruritus remains one of the most challenging management problems for gastroenterologists and hepatologists because its cause is unknown and conventional treatments are not consistently effective. The pruritus of cholestasis can be so severe that it may be an indication for liver transplantation even in the absence of overt hepatocellular failure.27Severe intractable pruritus of cholestasis constitutes a medical emergency and patients with chronic unrelieved pruritus of cholestasis may become suicidal. NEUROPHYSIOLOGY OF PRURITUS
Pruritus is an unpleasant sensation that stimulates the need to scratch. The sensation of peripheral pruritus is transmitted by unmyelinated C-fibers that transmit impulses at low velocities (0.5 m/sec). Pruritus is distinct from pain. In the skin, pruritus-sensing nerve fibers are located as free nerve endings at the dermoepithelial junction with projections into the epidermis. Current concepts of the neurophysiology
From the Division of Gastroenterology and Liver Disease, Beth Israel Medical Center, New York; and Albert Einstein College of Medicine, Bronx, New York (NVB); and the Department of Gastrointestinal and Liver Diseases, Academic Medical Centre, Amsterdam, The Netherlands (EAJ)
CLINICS IN LIVER DISEASE
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of the pruritus that originates from the skin suggest that when a few groups of nerve fibers are intermittently stimulated, pruritus ensues. Scratching results in neural inhibition, known as surround inhibition, which takes over the excitatory stimuli, and presumably results in the cessation of pruritus.%There have been no corresponding neurophysiological studies on the pruritus of cholestasis, however, and whether the neural mechanisms responsible for dermatological pruritus apply to the pruritus of cholestasis is unknown. In the majority of the patients, the pruritus associated with cholestasis is not readily relieved by scratching. This clinical observation suggests that this form of pruritus may arise from constant stimuli and that it may not be influenced by the neural inhibition that should result from scratching. Indeed, it was recently proposed that pruritus may arise as a result of derangement in a central inhibitory mechanism in the absence of pruritic stimuli generated in the periphery." The neurogenic stimuli that result in pruritus of peripheral origin are transmitted to the dorsal horn of the spinal cord, across the anterior commissure to the anterolateral spinothalamic pathway to the brainstem, thalamus, and cortex.29,43 Surgical ablation of lateral and anterior columns of the spinal cord in human beings abolishes the sensation of pruritus." Although data are limited to studies in experimental animals, it appears that higher cortical pathways exert major regulatory effects on the perception of pruritus and on the scratching reflex at the level of the spinal cord. Pruritus can arise de ~ O D Oin the central nervous system (CNS) and is a recognized manifestation of diseases that affect the CNS.2, 53, 66, 78 Thus, clinical evidence supporting the existence of a neurogenic pathway that mediates pruritus of central origin exists; however, the mechanisms that mediate this form of pruritus are uncertain. THE PRURITUS OF CHOLESTASIS
Pruritus may occur with any type of liver disease but is primarily associated with acute or chronic cholestasis. It has been estimated to occur in 20% to 50% of jaundiced patients,4O and in 80% of patients with primary biliary cirrhosis (PBC).34The intensity of the pruritus varies from mild to severe. In some patients, it may not interfere with regular activities and in others it may be intractable and lead to sleep deprivation. It can be persistent or intermittent and it may be generalized or localized to specific parts of the body. The soles of the feet and palms of the hands are common areas where the pruritus of cholestasis is first perceived. It can be transiently exacerbated by physiological states such as the premenstrual period in women (Jones, EA, unpublished observation, 1987). Patients with the pruritus of cholestasis describe the itch sensation as a burning, tingling or tickling sensation or as a feeling of bugs crawling over the body. The lack of satisfactory relief of the pruritus of cholestasis by scratching may lead patients to scratch with abrasive objects such as hair brushes and even steak knives. This results in
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skin lesions that are secondary to chronic scratching activity such as excoriations, lichenification and prurigo nodularis, which may become secondarily infected (Fig. 1).The skin of patients with the pruritus of cholestasis is devoid of pruritogenic lesions. The pruritus of cholestasis does not appear to correlate with the degree of cholestasis as assessed by serum activity of alkaline phosphatase, y-glutamyl transpeptidase, bilirubin, or bile acids.59 CAUSES
The cause of the pruritus of cholestasis is unknown. It has been postulated that this form of pruritus may occur as a result of the accumulation in plasma of substances that normally are synthesized and secreted efficiently by the liver into bile. This hypothesis is supported by the clinical observation that pruritus may subside spontaneously as the cholestatic liver disease progresses and hepatocellular function deteriorate^.^^ Thus, liver-produced pruritogens or cofactors of pruritogens may contribute to the pruritus of cholestasis. Bile acids, which normally are secreted into bile, accumulate in plasma and other body fluids and tissues in cholestasis.6,30, 35, 37 TheY have been considered as one group of substances that may mediate the pruritus of cholestasis, because under highly artificial experimental
Figure 1. Prurigo nodularis secondary to chronic scratching in a patient with PBC and pruritus (From Bergasa NV: The pruritis of cholestasis. Seminars in Dermatology 14:302-312; with permission).
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conditions they can induce pruritus.54,76 These findings do not confirm a role of bile acids in the mediation of this form of pruritus. The following observations do not support a role for bile acids as major mediators of the pruritus of cholestasis: in liver failure, when bile acids are elevated substantially, pruritus tends to cease; some patients with cholestasis and striking elevations of serum bile acids do not experience pruritus during the course of their disease; and pruritus can fluctuate and even remit spontaneously without concomitant changes in serum bile acid concentrations. A role for histamine, a pruritogenic substance, has also been considered in this form of pruritus. Histamine concentrations have been reported to be elevated in the plasma of patients with cholestasis and The skin of patients with this form of pruritus is devoid of the classical urticaria1 eruption characteristic of itch induced by histamine, however.
TRADITIONAL THERAPIES FOR THE PRURITUS OF CHOLESTASIS
The most widely administered treatment for the pruritus of cholesta22 Many sis has been the basic anion exchange resin ch~lestyramine.'~~ patients report ameliorations of their pruritus associated with resin treatment; however, in a substantial proportion of patients, relief of the symptom is at best only partial. Another resin, colestipol, is also available. These agents, which are given by mouth, are hydrophilic but insoluble in water and are not absorbed. They bind bile acids and other anionic compounds in the intestine, resulting in increased fecal excretion of bound substances. Therefore, these resins decrease the enterohepatic circulation of bile acids. Cholestyramine has also been reported to mediate a choleretic effect and by this mechanism it may promote the biliary clearance of a variety of The maximum recommended dose of cholestyramine is 16 g/24 h. The resins should be taken at least 2 hours apart from other medications to ensure adequate absorption of the latter. It is recommended that the resins be taken before and after breakfast to take advantage of the emptying of a full gall bladder after the overnight fast. A reasonable regimen is one packet before and one after breakfast, and if necessary, the addition of two additional packets over the rest of the day around meal times, when the gallbladder empties. Chronic ingestion of resins may lead to malabsorption. Cholestyramine has been reported to ameliorate the pruritus associated with polycythemia vera20and diseases which are not associated with elevated levels of circulating bile acids. Cholestyramine could affect the metabolism of different substances that may mediate the pruritus associated with uremia or polycythemia Vera, or alter the mechanisms which may underlie the pathogenesis of the pruritus associated with these systemic disorders. Thus, the reported ameliorations of the pruritus
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of cholestasis by cholestyramine treatment has not indicated that a specific class of substances mediates this form of pruritus. Antihistamines, the most common class of drug used for the symptomatic treatment of pruritic skin disorders, do not consistently induce ameliorations of this form of pruritus; in fact, it is rare to find a patient who experiences satisfactory relief from the pruritus of cholestasis associated with antihistamine therapy alone.=, 58 The reported apparent relief of this form of pruritus in some patients taking antihistamines may be attributed to the nonspecific sedative effect of this class of drugs. A complicating factor from the use of antihistamines is the xerostomia that results from their use and that worsens this symptom in patients with Sjogren's syndrome associated with PBC. The barbiturate phenobarbital has sedative effects as well as effects on the liver. This drug nonspecifically increases the activity of the hepatic microsomal enzyme system by enzyme induction. It is also a choleretic agent.74,77 In some patients, phenobarbital appears to partially ameliorate this form of pruritus15,36; however, whether the reported effects of this drug on pruritus are related to its effect on the liver where it may act by enhancing the excretion of pruritogens or to its nonspecific sedative properties, is unknown. The antibiotic rifampicin has emerged as a potential treatment for the pruritus of cholestasis. Hoesnsch et a1 reported ameliorations of this form of pruritus in some patients while studying the effects of rifampicin on serum bile acid levels in patients with PBC.46Interestingly, single doses of rifampicin (900 mg) significantly increased the 2 hr postprandial level of serum bile acids in patients with cirrhosis of the liver.32In a double-blind, crossover, randomized, short-term study that included nine patients with PBC, rifampicin therapy at doses of 150 mg orally twice a day or 150 mg three times a day in patients with serum bilirubin higher than 3 and lower than 3 mg/dl, respectively, was reported to be associated with ameliorations of the pruritus of cholestasis as assessed by a visual analogue scale of the perception of Other studies have reported similar results: although in one controlled study of patients with pruritus of cholestasis from different causes, this effect of rifampicin was not c ~ n f i r m e d In . ~ ~the liver, rifampicin increases the specific activity of hepatic microsomal drug metabolizing enzymes and it impairs the hepatic uptake of bilirubin, sulfobromophthalein and indocyanine green. Rifampicin can be hepatotoxic. Accordingly, careful monitoring of hepatic serum profile is strongly recommended during rifampicin treatment.4 The properties of rifampicin that result in the reported amelioration of pruritus are unknown.
Miscellaneous Therapies for the Pruritus of Cholestasis Other medications that have been administered to patients with the pruritus of cholestasis and reported to offer some relief include another
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enzyme inducer, flumecinol,83and the anticholestatic agents S-adenosylrnethionine3I and epomediol.41 These last two have been reported to reverse the cholestatic effects of several experimental agents. The lack of any completely satisfactory treatment for the pruritus of cholestasis has led to the application of experimental therapies without relevant modes of action that are difficult to categorize as a group. These include phototherapy to the lignocaine,s5 androgens?* hydroxyethylr~tosides,4~ and carbamazepine." These therapeutic modalities have been reported to induce transient ameliorations of pruritus in some patients in uncontrolled trials. In pilot studies, oral methotrexate has been associated with amelioration of the pruritis of cholestasis in some patients with PBC after approximately 6 months of therapy.7,12,51 The apparent decrease of this form of pruritus associated with methotrexate therapy may be related to a decrease in the degree of cholestasis and not to an effect on pruritus. Controlled trials of ursodeoxycholic acid for the treatment of patients with PBC have not confirmed a role of this medication as an effective therapy for the pruritus of cholestasis.M,57 These two drugs, methotrexate and ursodeoxycholic acid, are being studied for specific disease entities (notably PBC and primary sclerosing cholangitis [PSC]) and are not recommended for the treatment of the pruritus of cholestasis alone. The use of subhypnotic doses of the anesthetic propofol has been reported to ameliorate the pruritus of cholestasis.l6. Interestingly, propofol apparently is effective in the treatment of pruritus secondary to the spinal administration of m~rphine.'~ Heroic Measures for the Pruritus Of Cholestasis The failure of medical therapies discussed above to consistently ameliorate the pruritus of cholestasis has led to the application of therapeutic procedures which are invasive and aimed at the removal of a putative circulating pruritogenic substance. Such therapies include charcoal hemoperfusion,56 plasmapheresis,21 partial external diversion of and adsorbing-resin column plasma perfusion.' Transient ameliorations of pruritus in some patients associated with these measures have been reported in uncontrolled studies. The nature of any potentially relevant substance removed by these therapeutic approaches has not been defined. The fact that such measures have been tried emphasizes the lack of efficacy of conventional medications for the pruritus of cholestasis. THE ROLE OF SEDATION IN THE MANAGEMENT OF THE PRURITUS OF CHOLESTASIS The mental state of a patient who suffers from the pruritus of cholestasis can be seriously affected. Episodes of severe depression and suicidal ideations may occur. Consultation with a psychiatrist may be
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warranted. We have administered, with apparent benefit, a benzodiazepine (e.g., lorazepan) to patients with severe anxiety associated with the pruritus of cholestasis in whom hepatocellular function was good (Nora Bergasa, MD, and E. Anthony Jones, MD, unpublished observations, 1990).A hospital admission may be necessary as part of the management of a severe exacerbation of the pruritus of cholestasis to provide patients with a different environment from their usual one; this alone can sometimes be associated with relief in pruritus (N. V. Bergasa and E. A. Jones, unpublished, data, 1990). MANAGEMENT OF SKIN LESIONS FROM CHRONIC SCRATCHING
Lesions of prurigo nodularis and excoriations from chronic scratching can become infected. Appropriate cleaning of the lesions and specific antibiotic therapy may be necessary in some cases. EMERGING CONCEPTS ON THE PATHOGENESIS OF THE PRURITUS OF CHOLESTASIS The Endogenous Opioid System
Opiate agonist drugs that exert their biological effects by specific binding to opioid receptors are recognized as inducers of the sensation of pruritus and scratching behavior. This form of pruritus and scratching activity is considered to be of central origin, a concept that is supported by the following experimental and clinical observations: Morphine, an alkaloid which binds to opioid receptors, when administered intracisternally to cats, induces violent scratching5; the microinjection of morphine and the opioid agonist analogue DAMGO into the medullary dorsal horn of monkeys is associated with facial scratching which can be reversed by the opiate antagonist naloxone80; and the intrathecal administration of morphine (and, less commonly, its intravenous administration) and anesthetics that bind to opioid receptors are associated with pruritus which can also be relieved by the administration of naloxone5, 67 but which notably is not relieved by scratching.82 The administration of the opiate antagonist nalmefene to cholestatic patients with pruritus was associated with a cerebral reaction described as an opiate withdrawal-like reaction that occurred in the absence of the ingestion of opiate drugs by the patients and that did not occur in normal volunteers who took nalmefene.81In addition to the opiate withdrawal-like reaction, the cholestatic patients who received nalmefene experienced a relief in their pruritus, as assessed by a visual analogue scale.81The opiate withdrawal-like reaction precipitated by nalmefene in cholestatic patients led to the formulation of the hypothesis that in cholestasis, central opioidergic neurotransmission is increased and that
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this alteration contributes in part, to the pruritus of cholesta~is~~; therefore, the administration of opiate antagonists would be associated with ameliorations of the pruritus of cholestasis. Relief of intractable pruritus associated with the administration of naloxone was reported by Bernstein and Swift in 1979 in a patient with PBC.I4The concept of increased opioidergic tone in cholestasis implicates a specific class of substances, endogenous opioids, in its pathogenesis. The presence of naloxonereversible antinociception in a rat model of cholestasis further supports the concept that increased opioidergic neurotransmission contributes to the pathophysiology of this syndrome.'O
Behavioral Studies on the Pruritus of Cholestasis: Use Of Quantitative Methodology The measurement of the concentration of substances that circulate in human plasma and which may rise as a result of cholestasis has not led to the identification of specific substances that are implicated may be associated in the pruritus of cholestasis, even if those substances are associated with pruritus and scratching under experimental conditions. Until recently, clinical trials of therapies for the pruritus of cholestasis have utilized subjective efficacy endpoints. Pruritus is a perception and because it is a perception it cannot be objectively quantitated. The need to apply objective quantitative methodology in studies of the efficacy of therapies for the pruritus of cholestasis has been recognized for years.28,70, 71 The sensation of pruritus or itch elicits the need to scratch.&To objectively evaluate scratching behavior, the authors developed an instrument that allowed for the quantitation of scratching activity independent of body movement.79
Studies of Opiate Antagonist Drugs that Apply Quantitative Methodology The hypothesis that increased opioidergic neurotransmission contributes to the pathophysiology of cholestasis and to the pruritus associated with it was tested in clinical studies, including a double-blind, placebocontrolled trial of the opiate antagonist naloxone in patients with cholestasis and pruritus.8, Naloxone infusions (0.2 Fg/kg/min preceded by an intravenous bolus injection of 0.4 mg of naloxone), in contrast to placebo infusions, were associated with a decrease in the perception of pruritus, as assessed by the visual analogue scale, and a decrease in scratching a~tivity.~ These findings support a role for the endogenous opioid system in the pathogenesis of the pruritus of cholestasis. An important result of this study was that some patients exhibited a circadian rhythm in their scratching behavior, suggesting that the scratching monitoring device recorded a true biological activity (Fig. 2). Administration of naloxone infusions (preceded by bolus injections,
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Hours
Figure 2. Mean hourly scratching activity during 96 hours of quantitation in a patient with pruritus of cholestasis. The continuous solid line indicates the 24-hour rhythm that best fits the observations. (From Bergasa NV, Alling DW, Talbot TL, et al: Naloxone ameliorates the pruritis of cholestasis. Results of a double-blind randomized placebo-controlled trial. Ann lntl Med 123:161-167, 1995; with permission.)
as described above) with dose titration to achieve a subjective decrease in pruritus is a reasonable approach to treat patients with intractable pruritus, a condition that can be considered a medical emergency. Naloxone infusions were administered at doses ranging from 0.2 to 1.26 pg/ kg/min to patients with the pruritus of cholestasis who were awaiting liver transplantation, with reported subjective relief and no deleterious side effe~ts.4~ The preferred mode of administration for naloxone is parenteral because of its low oral bioavailability. Thus, naloxone is impractical for the long term management of patients with the pruritus of chronic cholestasis. Nalmefene is a specific opiate antagonist which is orally bioavailable, more potent than naloxone, and has a more prolonged In, an open label study, nalpharmacological action than n a l ~ x o n e . ~ ~ mefene administration was associated with a significant subjective amelioration of pruritus, as measured by a visual analogue scale of pruritus, and a significant decrease in scratching activity (Figs. 3 and 4).*Nalmefene was administered at doses much lower than in a previous studys1 in an attempt to prevent the opiate withdrawal-like reaction that had been reported to occur when small doses of nalmefene were administered to patients with the pruritus of cholestasis.sl Although some reactions suggestive of an opiate withdrawal-like reaction were observed, their frequency and severity were much less than those previously reported.s1 Oral nalmefene currently is not licensed; however, another potent opiate antagonist that also is orally bioavailable, naltrexone, can be administered orally and has been available for several years. The concern regarding the administration of the drug naltrexone is its potential hepatotoxicity, which appears to be dose related, and its tolerability (E. Anthony Jones, MD, unpublished observations, 1996).63The rationale for its administration, however, would be the same as that for naloxone and nalmefene. Naltrexone at doses of 50 mg per day has been studied in a placebo-controlled study of patients with the pruritus of cholestasis
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nalmefene
Figure 3. The perception of pruritus as assessed by a visual analogue scale for pruritus before and during nalmefene therapy in a group of patients with cholestatic liver disease. There was a significant decrease in the mean visual analogue score for pruritus on nalmefene when compared to the mean score prior to treatment (baseline). (From Bergasa NV, Alling DW, Talbot TL, et al: Relief from the intractable pruritus of chronic cholestasis associated with oral nalrnefene therapy. Hepatology 14:A154, 1991; with permission.)
without apparent toxicity and with subjective relief of their pruritus as assessed subjectively.88
The Serotonin System in the Pruritus of Cholestasis
The serotonin system appears to be involved in the transmission of nociception (i.e., sensation of pain).69By analogy with the opioid system, it seems possible that the serotonin system may also be involved in the mediation of pruritus. When the serotonin receptor type 3 antagonist ondansetron (8 mg) was administered intravenously to patients with the pruritus of cholestasis, subjective relief of pruritus lasting several hours was In one placebo controlled study, ondansetron, but not placebo injection was also associated with subjective relief of this form of pruritus." In a short term placebo-controlled study intravenously and orally administered ondansetron did not decrease scratching activity in The short duration of this patients with the pruritus of chole~tasis.~~ study may not have allowed the full effects of ondansetron to become apparent, because scratching activity may have become habitual in the patients studied.26,6o Indeed, a prolonged period of administration of
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c
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Figure 4. Mean log,, hourly scratching activity at baseline and during nalmefene therapy in a group of patients with the pruritus of cholestasis. (From Bergasa NV, Alling DW, Talbot TL, et al: Relief from the intractable pruritus of chronic cholestasis associated with oral nalmefene therapy. Hepatology 14:A154, 1991; with permission.)
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ondansetron (e.g./ several weeks) may be necessary for an effect on scratching activity to become apparent. Increased opioidergic neurotransmission in cholestasis" may alter serotoninergic neurotransmission since these two neurotransmitter systems have neuronal connections in the brain. Experiments in laboratory animals suggest that opioid-induced analgesia can be blocked by ond a n ~ e t r o n Experiments .~~ demonstrating increased serotonergic neurotransmission in animal models of cholestasis, however, have not been reported. CONCLUSION
The pruritus of cholestasis is a difficult clinical problem to manage and requires scientific studies to understand its pathogenesis. The application of quantitative methodology in clinical studies has proven to be an important approach in indentifying a specific neurotransmitter system that appears to be involved in the mediation of this form of pruritus. The use of resins (e.g./ cholestyramine) and the antibiotic rifampicin appears to offer relief of the pruritus of cholestasis in some patients, as
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evaluated by subjective methodology. However, the mechanisms of the ameliorations associated with the administration of these agents have not been determined. The concept that neurotransmitter systems are involved in the mediation of the pruritus of cholestasis is evolving. Recently, data that have emerged from studies of animal models and patients support the hypothesis that increased central opioidergic neurotransmission contributes to the pathophysiology of cholestasis and potentially to the pruritus of cholestasis. The data supporting this hypothesis provide a rationale for the use of opiate antagonist drugs for the treatment of the pruritus of cholestasis, and drugs of this class have been shown to ameliorate this form of pruritus in controlled clinical studies. The factors that lead to alterations in opioidergic neurotransmission in cholestasis are uncertain, but the cholestatic liver may be a source of endogenous opioid agonist peptides in chole~tasis.’~
References 1. Alarabi AA, Wikstrom B, Loof L, et al: Treatment of pruritus in cholestatic jaundice by bilirubin- and bile acid-adsorbing resin column plasma perfusion. Scand J Gastroenterol 27223-226, 1992 2. Andreev V, Petkov I: Skin manifestations associated with tumours of the brain. Br Med Derm 92:675-678, 1974 3. Bachs L, Parks A, Elena M, et al: Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis [see comments]. Lancet 1:574-576, 1989 4. Bachs L, Parks A, Elena M, et al: Effects of long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology 102:2077-2080, 1992 5. Ballantyne JC, Loach AB, Carr DB: Itching after epidural and spinal opiates. Pain 33:149-160, 1988 6. Bartholomew TC, Summerfield JA, Billing BH, et al: Bile acid profiles of human serum and skin interstitial fluid and their relationship to pruritus studied by gas chromatography-mass spectrometry. Clin Sci 63:65-73, 1982 7. Bergasa N, Hoofnagle J, Kliener D, et al: Methotrexate (MTX) therapy for primary biliary cirrhosis: interim evaluation of an open label study. Hepatology 16:516, 1992 8. Bergasa NV, Talbot TL, Schmitt JP, et al: Relief from the intractable pruritus of chronic cholestasis associated with oral nalmefene therapy. Hepatology 14:A154, 1991 9. Bergasa NV, Alling DW, Talbot TL, et al: Naloxone ameliorates the pruritus of cholestasis: results of a double-blind randomized placebo-controlled trial. Ann Int Med 123:161-167, 1995 10. Bergasa NV, Alling DW, Vergalla J, et al: Cholestasis in the male rat is associated with naloxone-reversible antinociception. J Hepatol 20:85-90, 1994 11. Bergasa NV, Jones EA: The pruritus of cholestasis: potential pathogenic and therapeutic implications of opioids. Gastroenterology 108:1582-1588, 1995 12. Bergasa NV, Jones EA, Kleiner D, et al: Pilot study of low-dose oral methotrexate for the treatment of primary biliary cirrhosis. Am J Gastroenterol 91:295-299, 1996 13. Bergasa NV, Sabol SL, Young SW, et a1 Cholestasis is associated with preproenkephalin mRNA expression in the adult rat liver. Am J Physiol268:346-354, 1995 14. Bernstein JE, Swift R: Relief of intractable pruritus with naloxone. Arch Dermatol 115:1366-1367, 1979 15. Bloomer JR, Boyer J L Phenobarbital effects in cholestatic liver diseases. Ann Intern Med 82:310-317, 1975 16. Borgeat A, Wilder-Smith 0, Mentha G, et al: Propofol and cholestatic pruritus. American Journal of Gastroenterology 87672474, 1992
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17. Borgeat A, Wilder-Smith 0, Saiah M, et a1 Subhypnotic doses of propofol relieve pruritus induced by epidural and intrathecal morphine. Anesthesiology 76:510-512, 1992 18. Borgeat A, Wilder-Smith OHG, Mentha G: Subhypnotic doses of propofol relieve pruritus associated with liver disease. Gastroenterology 104:244-247, 1993 19. Carey CJ: Lowering of serum bile acid concentrations and relief of pruritus in jaundiced patients fed a bile acid sequestering resin. Journal Laboratory Clinical Medicine 56:797798, 1961 20. Chanarin I, Szur I: Relief of intractable pruritus in polycythaemia rubra Vera with cholestyramine. Br J Haematol 29:669-670, 1970 21. Cohen LB, Ambinder EP, Wolke AM, et al: Role of plasmapheresis in primary biliary cirrhosis. Gut 26:291-294, 1985 22. Datta D, Sherlock S: Cholestyramine for long term relief of the pruritus complicating intrahepatic cholestasis. Gastroenterology 50323-332, 1966 23. Dixon R, Gentile J, Hsu H-B, et a1 Nalmefene: Safety and kinetics after single and multiple oral doses of a new opioid antagonist. J Clin Pharmacol 27233-239, 1987 24. Donovan G, Kidwell M: Benign recurrent intrahepatic cholestasis: Relief of pruritus with carbamazepine. Gastroenterology 94:A536, 1988 25. Duncan JS, Kennedy HJ, Triger DR Treatment of pruritus due to chronic obstructive liver disease. Br Med J (Clin Res Ed) 289:1984 26. Edwards AE, Shellow VR, Wright ET, et al: Pruritic skin disease, psychological stress and the itch sensation. Archives of Dermatology 112:339-343, 1976 27. Elias E: Liver Transplantation. J Ry Coll Physc Lndon 27224-232, 1993 28. Felix R, Shuster S A new method for the measurement of itch and the response to treatment. Br J Dermatol93:303-312, 1975 29. Fjellner B: Experimental and clinical pruritus. Acta Derm Venereol Suppl (Stockh) 972-34, 1981 30. Freedman MR, Holzbach RT, Ferguson DR Pruritus in cholestasis: no direct causative role for bile acid retention. Am J Med 701011-1016, 1981 31. Frezza M, Surrenti C, Manzillo G, et al: Oral S-adenosylmethionine in the symptomatic treatment of intrahepatic cholestasis. A double-blind, placebo-controlled study. Gastroenterology 99:211-215, 1990 32. Galeazzi R Rifampicin-induced elevation of serum bile acids in man. Dig Dis Sci 25108-112, 1980 33. Garbutt JT, Kenney TJ: Effect of cholestyramine on bile acid metabolism in normal man. J Clin Invest 51:2781-2789,1972 34. Ghent C N Itch Mechanisms and Managements of Pruritus. In Bernhard JD (ed): Cholestatic pruritus. New York, McGraw-Hill Inc, 1994, pp 229-242 35. Ghent CN, Bloomer JR Itch in liver disease: facts and speculations. Yale J Biol Med 52~77-82,1979 36. Ghent CN, Bloomer JR, Hsia YE: Safety and efficacy of longterm treatment of familiar intrahepatic cholestasis with phenobarbital. J Pediat 93:127-132,1978 37. Ghent CN, Bloomer JR, Klatskin G: Elevations in skin tissue levels of bile acids in human cholestasis: Relation to serum levels and to pruritus. Gastroenterology 73:1125-1130, 1977 38. Ghent CN, Carruthers SG: Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial. Gastroenterology 94488493, 1988 39. Gittlen SD, Schulman ES, Maddrey WC: Raised histamine concentrations in chronic cholestatic liver disease. Gut 31:96-99, 1990 40. Gleeson D, Boyer J: Oxford textbook of clinical hepatology. In McIntyre N, Benhamou JP, Bircher J, et a1 (eds): J Intrahepatic cholestasis. New York, Oxford University Press, 1991, pp 1087-1107 41. Gonzalez M, Iglesias J, Tiribelli C, et al: Epomediol ameliorates pruritus in patients with intrahepatic cholestasis of pregnancy. J Hepatol 16241-242, 1992 42. Greaves WW, Wall P D Pathophysiology of itching. The Lancet 348:93%940, 1996 43. Guyton A: Textbook of Medical Physiology. In Somatic sensations: 11: Pain, headache, and thermal sensations. Philadelphia, WB Saunders, 1991, pp 520-523
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44. Heathcote E, Cauch-Dudek K, Walker V, et al: The Canadian multicenter doubleblind randomized controlled trial of ursodeoxycholic acid in primary biliary cirrhosis. Hepatology 19:1149-1156, 1994 45. Hishon S, Rose JD, Hunter J O The relief of pruritus in primary biliary cirrhosis by hydroxyethylrutosides. Brit J Dermatol 105:457459, 1981 46. Hoensch HP, Balzer K, Dylewizc P, et al: Effect of rifampicin treatment on hepatic drug metabolism and serum bile acids in patients with primary biliary cirrhosis. Eur J Clin Pharmacol28:475477, 1985 47. IIagan MB, Garcia L, Rothstein K, et al: Naloxone infusions for management of intractable pruritus in cholestatic liver transplant candidates. Hepatology 24:696, 1996 48. Jaffe J, Martin W The pharmacologic basis of therapeutics. In Gilman A, Goodman L, Rall T (eds): Opioid analgesics and antagonists (ed 7). New York, Macmillan, 1985, pp 491-531 49. Jones EA, Bergasa NV The pruritus of cholestasis: From bile acids to opiate agonists. Hepatology 113884-887, 1990 50. Jones EA, Bergasa Nv: The pruritus of cholestasis and the opioid system. J Am Med ASSOC 268~3359-3367,1992 51. Kaplan MM, Knox TA: Treatment of primary biliary cirrhosis with low-dose weekly methotrexate [see comments]. Gastroenterology 101:1332-1338, 1991 52. Kiefel JM, Cooper ML, Bodnar RJ: Serotonin receptor subtype antagonists in the medial ventral medulla inhibit mesencephalic opiate analgesia. Brain Res 597331-338, 1992 53. King C, Huff J, Jorizzo J: Unilateral neurogenic pruritus: proxysmal itching associated with central nervous system lesions. AM Int Med 97222-223, 1982 54. Kirby J, Heaton KW, Burton JL: Pruritic effect of bile salts. Br Med J 4:693-695, 1974 55. Koenigstein H: Experimental study of itch stimuli in animals. Arch Dermatol Syphilol 57828-849, 1948 56. Lauterberg B, Taswell H, Pineda A, et al: Treatment of pruritus of cholestasis by plasma perfusion through USP-charcoal-coated glass beads. Lancet 253-55, 1980 57. Lindor KD, Dickson RE, Baldus WP, et al: Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 106:1284-1290, 1994 58. Lloyd-Thomas HGL, Sherlock S Testosterone therapy for the pruritus of obstructive jaundice. Brit Med J 21289-1291, 1952 59. Long RG, Scheuer PJ, Sherlock S: Presentation and course of asymptomatic primary biliary cirrhosis. Gastroenterology 72:1204-1207, 1977 60. Lowitt MH, Bemhard JD: Pruritus. Sem Neurol 123374-384, 1992 61. Maggiore G, Grifeo S, DeGiacomo C, et al: Phototherapy for pruritus in chronic cholestasis of childhood. Europ J Pediat 139:90-91, 1982 62. Michel M, Bolger G, Weissman BA: Binding of a new opiate antagonist, nalmefene, to rat brain membranes. Meth Find Exptl Clin Pharmacol 7175-177, 1985 63. Naltrexone: ln Physicians Desk Reference. Montvale, New Jersey, Medical Economics Company, 1996, pp 957-959 64. Nathan PW Touch and surgical division of the anterior quadrant of the spinal cord. J Neurol Neursurg Psych 53:935-939, 1990 65. O’Donohue JW, Haigh C, Williams R Ondansetron in the treatment of the pruritus of cholestasis: A randomised controlled trial. Gastroenterology 112:A1349, 1997 66. Osterman I? Paroxysmal itching in multiple sclerosis. Br J Dermatol 95:555-558, 1976 67. Parker F Cecil textbook of medicine. In Wyngardeen JB, Smith LH (eds): Skin Diseases. Philadelphia, WB Saunders, 1988, pp 2300-2353 68. Procacci P, Maresco M: Central pruritus. Case report. Pain 45:307-308, 1991 69. Richardson 8: Serotonin and nociception. Ann N Y Acad Sci 600:511-520, 1990 70. Savin J, Paterson W, Oswald I: Scratching during sleep. Lancet 2296-297, 1973 71. Savin J, Paterson W, Oswald I, et al: Further studies of scratching during sleep. Br J Dermatol93:297-302, 1975 72. Schwoer H, Hartmann H, Ramadori G: Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: Effectiveness of ondansetron. Pain 61:33-37, 1995 73. Schworer H, Ramadori G: Improvement of cholestatic pruritus by ondansetron. Lancet 341:1277, 1993
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74. Sharp HL, Carey JJ, White JG, et a1 Cholestyramine therapy in patients with a paucity of intrahepatic bile ducts. J Pediatr 71:723-736, 1967 75. Silberberg DS, Iaina A, Reisin E, et al: Cholestyramine in uraemic pruritus. Br Med J 1:752-753, 1977 76. Stiehl A: Bile acids and bile acid sulfates in the skin of patients with cholestasis and pruritus. Z Gastroenterol 12:121-124, 1974 77. Stiehl A, Thaler MM, Admirand W H Effects of phenobarbital on bile salt metabolism in cholestasis due to intrahepatic bile duct hypoplasia. Pediatrics 51:992-997, 1973 78. Sullivan M, Drake M: Unilateral pruritus and Nocardia brain abscess. Neurology 123~1527-1530,1984 79. Talbot TL, Schmitt JM, Bergasa NV, et al: Application of piezo film technology for the quantitative assessment of pruritus. Biomed Instrum Techno1 25:400-403, 1991 80. Thomas DA, Williams GM, Iwata K, et al: Effects of central administration of opioids on facial scratching in monkeys. Brain Research 585:315-317, 1992 81. Thomton JR, Losowsky MS: Opioid peptides and primary biliary cirrhosis. Br Med J 2971501-1504, 1988 82. Tuckett RP, Denman ST, Chapman R, et al: Pruritus, cutaneous pain, and eccrine gland and sweating disorders. J Am Acad Dermatol 11:lOOO-1006, 1984 83. Turner IB, Rawlins MD, Wood P, et al: Flumecimol for the treatment of pruritus associated with primary biliary cirrhosis. Aliment Pharmacol Ther 8:337-342, 1994 84. Greaves MW, Wall P D Pathophysiology of itching. The Lancet 348:938-940, 1996 85. Watson W Intravenous lignocaine for relief of intratable itch. Lancet 1:211, 1973 86. Whitington E,' Whitington G: Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis. Gastroenterology 95:130136, 1988 87. Woolf GM, Reynold TB: Failure of rifampicin to relieve pruritus in chronic liver disease. J Clin Gastroenterol 12:174-177, 1990 88. Wolfhagen FHJ, Stemieri E, Hop WCJ et al: Oral naltrexone treatment for cholestatic pruritis: A double-blind, placebo-controlled study. Gastroenterology 113:264-1269,1997
Address reprint requests to Nora V. Bergasa, MD 18 Baird Hall First Avenue at 16th Street New York. NY 10021
1089-3261/98 $8.00
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THE PRURITUS OF CHOLESTASIS Evolving Pathogenic Concepts Suggest New Therapeutic Options Nora V. Bergasa, MD, and E. Anthony Jones, MD
"Like lying on a bed of cactus" is how one patient with the pruritus of cholestasis described her This form of pruritus remains one of the most challenging management problems for gastroenterologists and hepatologists because its cause is unknown and conventional treatments are not consistently effective. The pruritus of cholestasis can be so severe that it may be an indication for liver transplantation even in the absence of overt hepatocellular failure.27Severe intractable pruritus of cholestasis constitutes a medical emergency and patients with chronic unrelieved pruritus of cholestasis may become suicidal. NEUROPHYSIOLOGY OF PRURITUS
Pruritus is an unpleasant sensation that stimulates the need to scratch. The sensation of peripheral pruritus is transmitted by unmyelinated C-fibers that transmit impulses at low velocities (0.5 m/sec). Pruritus is distinct from pain. In the skin, pruritus-sensing nerve fibers are located as free nerve endings at the dermoepithelial junction with projections into the epidermis. Current concepts of the neurophysiology
From the Division of Gastroenterology and Liver Disease, Beth Israel Medical Center, New York; and Albert Einstein College of Medicine, Bronx, New York (NVB); and the Department of Gastrointestinal and Liver Diseases, Academic Medical Centre, Amsterdam, The Netherlands (EAJ)
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of the pruritus that originates from the skin suggest that when a few groups of nerve fibers are intermittently stimulated, pruritus ensues. Scratching results in neural inhibition, known as surround inhibition, which takes over the excitatory stimuli, and presumably results in the cessation of pruritus.%There have been no corresponding neurophysiological studies on the pruritus of cholestasis, however, and whether the neural mechanisms responsible for dermatological pruritus apply to the pruritus of cholestasis is unknown. In the majority of the patients, the pruritus associated with cholestasis is not readily relieved by scratching. This clinical observation suggests that this form of pruritus may arise from constant stimuli and that it may not be influenced by the neural inhibition that should result from scratching. Indeed, it was recently proposed that pruritus may arise as a result of derangement in a central inhibitory mechanism in the absence of pruritic stimuli generated in the periphery." The neurogenic stimuli that result in pruritus of peripheral origin are transmitted to the dorsal horn of the spinal cord, across the anterior commissure to the anterolateral spinothalamic pathway to the brainstem, thalamus, and cortex.29,43 Surgical ablation of lateral and anterior columns of the spinal cord in human beings abolishes the sensation of pruritus." Although data are limited to studies in experimental animals, it appears that higher cortical pathways exert major regulatory effects on the perception of pruritus and on the scratching reflex at the level of the spinal cord. Pruritus can arise de ~ O D Oin the central nervous system (CNS) and is a recognized manifestation of diseases that affect the CNS.2, 53, 66, 78 Thus, clinical evidence supporting the existence of a neurogenic pathway that mediates pruritus of central origin exists; however, the mechanisms that mediate this form of pruritus are uncertain. THE PRURITUS OF CHOLESTASIS
Pruritus may occur with any type of liver disease but is primarily associated with acute or chronic cholestasis. It has been estimated to occur in 20% to 50% of jaundiced patients,4O and in 80% of patients with primary biliary cirrhosis (PBC).34The intensity of the pruritus varies from mild to severe. In some patients, it may not interfere with regular activities and in others it may be intractable and lead to sleep deprivation. It can be persistent or intermittent and it may be generalized or localized to specific parts of the body. The soles of the feet and palms of the hands are common areas where the pruritus of cholestasis is first perceived. It can be transiently exacerbated by physiological states such as the premenstrual period in women (Jones, EA, unpublished observation, 1987). Patients with the pruritus of cholestasis describe the itch sensation as a burning, tingling or tickling sensation or as a feeling of bugs crawling over the body. The lack of satisfactory relief of the pruritus of cholestasis by scratching may lead patients to scratch with abrasive objects such as hair brushes and even steak knives. This results in
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skin lesions that are secondary to chronic scratching activity such as excoriations, lichenification and prurigo nodularis, which may become secondarily infected (Fig. 1).The skin of patients with the pruritus of cholestasis is devoid of pruritogenic lesions. The pruritus of cholestasis does not appear to correlate with the degree of cholestasis as assessed by serum activity of alkaline phosphatase, y-glutamyl transpeptidase, bilirubin, or bile acids.59 CAUSES
The cause of the pruritus of cholestasis is unknown. It has been postulated that this form of pruritus may occur as a result of the accumulation in plasma of substances that normally are synthesized and secreted efficiently by the liver into bile. This hypothesis is supported by the clinical observation that pruritus may subside spontaneously as the cholestatic liver disease progresses and hepatocellular function deteriorate^.^^ Thus, liver-produced pruritogens or cofactors of pruritogens may contribute to the pruritus of cholestasis. Bile acids, which normally are secreted into bile, accumulate in plasma and other body fluids and tissues in cholestasis.6,30, 35, 37 TheY have been considered as one group of substances that may mediate the pruritus of cholestasis, because under highly artificial experimental
Figure 1. Prurigo nodularis secondary to chronic scratching in a patient with PBC and pruritus (From Bergasa NV: The pruritis of cholestasis. Seminars in Dermatology 14:302-312; with permission).
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conditions they can induce pruritus.54,76 These findings do not confirm a role of bile acids in the mediation of this form of pruritus. The following observations do not support a role for bile acids as major mediators of the pruritus of cholestasis: in liver failure, when bile acids are elevated substantially, pruritus tends to cease; some patients with cholestasis and striking elevations of serum bile acids do not experience pruritus during the course of their disease; and pruritus can fluctuate and even remit spontaneously without concomitant changes in serum bile acid concentrations. A role for histamine, a pruritogenic substance, has also been considered in this form of pruritus. Histamine concentrations have been reported to be elevated in the plasma of patients with cholestasis and The skin of patients with this form of pruritus is devoid of the classical urticaria1 eruption characteristic of itch induced by histamine, however.
TRADITIONAL THERAPIES FOR THE PRURITUS OF CHOLESTASIS
The most widely administered treatment for the pruritus of cholesta22 Many sis has been the basic anion exchange resin ch~lestyramine.'~~ patients report ameliorations of their pruritus associated with resin treatment; however, in a substantial proportion of patients, relief of the symptom is at best only partial. Another resin, colestipol, is also available. These agents, which are given by mouth, are hydrophilic but insoluble in water and are not absorbed. They bind bile acids and other anionic compounds in the intestine, resulting in increased fecal excretion of bound substances. Therefore, these resins decrease the enterohepatic circulation of bile acids. Cholestyramine has also been reported to mediate a choleretic effect and by this mechanism it may promote the biliary clearance of a variety of The maximum recommended dose of cholestyramine is 16 g/24 h. The resins should be taken at least 2 hours apart from other medications to ensure adequate absorption of the latter. It is recommended that the resins be taken before and after breakfast to take advantage of the emptying of a full gall bladder after the overnight fast. A reasonable regimen is one packet before and one after breakfast, and if necessary, the addition of two additional packets over the rest of the day around meal times, when the gallbladder empties. Chronic ingestion of resins may lead to malabsorption. Cholestyramine has been reported to ameliorate the pruritus associated with polycythemia vera20and diseases which are not associated with elevated levels of circulating bile acids. Cholestyramine could affect the metabolism of different substances that may mediate the pruritus associated with uremia or polycythemia Vera, or alter the mechanisms which may underlie the pathogenesis of the pruritus associated with these systemic disorders. Thus, the reported ameliorations of the pruritus
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of cholestasis by cholestyramine treatment has not indicated that a specific class of substances mediates this form of pruritus. Antihistamines, the most common class of drug used for the symptomatic treatment of pruritic skin disorders, do not consistently induce ameliorations of this form of pruritus; in fact, it is rare to find a patient who experiences satisfactory relief from the pruritus of cholestasis associated with antihistamine therapy alone.=, 58 The reported apparent relief of this form of pruritus in some patients taking antihistamines may be attributed to the nonspecific sedative effect of this class of drugs. A complicating factor from the use of antihistamines is the xerostomia that results from their use and that worsens this symptom in patients with Sjogren's syndrome associated with PBC. The barbiturate phenobarbital has sedative effects as well as effects on the liver. This drug nonspecifically increases the activity of the hepatic microsomal enzyme system by enzyme induction. It is also a choleretic agent.74,77 In some patients, phenobarbital appears to partially ameliorate this form of pruritus15,36; however, whether the reported effects of this drug on pruritus are related to its effect on the liver where it may act by enhancing the excretion of pruritogens or to its nonspecific sedative properties, is unknown. The antibiotic rifampicin has emerged as a potential treatment for the pruritus of cholestasis. Hoesnsch et a1 reported ameliorations of this form of pruritus in some patients while studying the effects of rifampicin on serum bile acid levels in patients with PBC.46Interestingly, single doses of rifampicin (900 mg) significantly increased the 2 hr postprandial level of serum bile acids in patients with cirrhosis of the liver.32In a double-blind, crossover, randomized, short-term study that included nine patients with PBC, rifampicin therapy at doses of 150 mg orally twice a day or 150 mg three times a day in patients with serum bilirubin higher than 3 and lower than 3 mg/dl, respectively, was reported to be associated with ameliorations of the pruritus of cholestasis as assessed by a visual analogue scale of the perception of Other studies have reported similar results: although in one controlled study of patients with pruritus of cholestasis from different causes, this effect of rifampicin was not c ~ n f i r m e d In . ~ ~the liver, rifampicin increases the specific activity of hepatic microsomal drug metabolizing enzymes and it impairs the hepatic uptake of bilirubin, sulfobromophthalein and indocyanine green. Rifampicin can be hepatotoxic. Accordingly, careful monitoring of hepatic serum profile is strongly recommended during rifampicin treatment.4 The properties of rifampicin that result in the reported amelioration of pruritus are unknown.
Miscellaneous Therapies for the Pruritus of Cholestasis Other medications that have been administered to patients with the pruritus of cholestasis and reported to offer some relief include another
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enzyme inducer, flumecinol,83and the anticholestatic agents S-adenosylrnethionine3I and epomediol.41 These last two have been reported to reverse the cholestatic effects of several experimental agents. The lack of any completely satisfactory treatment for the pruritus of cholestasis has led to the application of experimental therapies without relevant modes of action that are difficult to categorize as a group. These include phototherapy to the lignocaine,s5 androgens?* hydroxyethylr~tosides,4~ and carbamazepine." These therapeutic modalities have been reported to induce transient ameliorations of pruritus in some patients in uncontrolled trials. In pilot studies, oral methotrexate has been associated with amelioration of the pruritis of cholestasis in some patients with PBC after approximately 6 months of therapy.7,12,51 The apparent decrease of this form of pruritus associated with methotrexate therapy may be related to a decrease in the degree of cholestasis and not to an effect on pruritus. Controlled trials of ursodeoxycholic acid for the treatment of patients with PBC have not confirmed a role of this medication as an effective therapy for the pruritus of cholestasis.M,57 These two drugs, methotrexate and ursodeoxycholic acid, are being studied for specific disease entities (notably PBC and primary sclerosing cholangitis [PSC]) and are not recommended for the treatment of the pruritus of cholestasis alone. The use of subhypnotic doses of the anesthetic propofol has been reported to ameliorate the pruritus of cholestasis.l6. Interestingly, propofol apparently is effective in the treatment of pruritus secondary to the spinal administration of m~rphine.'~ Heroic Measures for the Pruritus Of Cholestasis The failure of medical therapies discussed above to consistently ameliorate the pruritus of cholestasis has led to the application of therapeutic procedures which are invasive and aimed at the removal of a putative circulating pruritogenic substance. Such therapies include charcoal hemoperfusion,56 plasmapheresis,21 partial external diversion of and adsorbing-resin column plasma perfusion.' Transient ameliorations of pruritus in some patients associated with these measures have been reported in uncontrolled studies. The nature of any potentially relevant substance removed by these therapeutic approaches has not been defined. The fact that such measures have been tried emphasizes the lack of efficacy of conventional medications for the pruritus of cholestasis. THE ROLE OF SEDATION IN THE MANAGEMENT OF THE PRURITUS OF CHOLESTASIS The mental state of a patient who suffers from the pruritus of cholestasis can be seriously affected. Episodes of severe depression and suicidal ideations may occur. Consultation with a psychiatrist may be
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warranted. We have administered, with apparent benefit, a benzodiazepine (e.g., lorazepan) to patients with severe anxiety associated with the pruritus of cholestasis in whom hepatocellular function was good (Nora Bergasa, MD, and E. Anthony Jones, MD, unpublished observations, 1990).A hospital admission may be necessary as part of the management of a severe exacerbation of the pruritus of cholestasis to provide patients with a different environment from their usual one; this alone can sometimes be associated with relief in pruritus (N. V. Bergasa and E. A. Jones, unpublished, data, 1990). MANAGEMENT OF SKIN LESIONS FROM CHRONIC SCRATCHING
Lesions of prurigo nodularis and excoriations from chronic scratching can become infected. Appropriate cleaning of the lesions and specific antibiotic therapy may be necessary in some cases. EMERGING CONCEPTS ON THE PATHOGENESIS OF THE PRURITUS OF CHOLESTASIS The Endogenous Opioid System
Opiate agonist drugs that exert their biological effects by specific binding to opioid receptors are recognized as inducers of the sensation of pruritus and scratching behavior. This form of pruritus and scratching activity is considered to be of central origin, a concept that is supported by the following experimental and clinical observations: Morphine, an alkaloid which binds to opioid receptors, when administered intracisternally to cats, induces violent scratching5; the microinjection of morphine and the opioid agonist analogue DAMGO into the medullary dorsal horn of monkeys is associated with facial scratching which can be reversed by the opiate antagonist naloxone80; and the intrathecal administration of morphine (and, less commonly, its intravenous administration) and anesthetics that bind to opioid receptors are associated with pruritus which can also be relieved by the administration of naloxone5, 67 but which notably is not relieved by scratching.82 The administration of the opiate antagonist nalmefene to cholestatic patients with pruritus was associated with a cerebral reaction described as an opiate withdrawal-like reaction that occurred in the absence of the ingestion of opiate drugs by the patients and that did not occur in normal volunteers who took nalmefene.81In addition to the opiate withdrawal-like reaction, the cholestatic patients who received nalmefene experienced a relief in their pruritus, as assessed by a visual analogue scale.81The opiate withdrawal-like reaction precipitated by nalmefene in cholestatic patients led to the formulation of the hypothesis that in cholestasis, central opioidergic neurotransmission is increased and that
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this alteration contributes in part, to the pruritus of cholesta~is~~; therefore, the administration of opiate antagonists would be associated with ameliorations of the pruritus of cholestasis. Relief of intractable pruritus associated with the administration of naloxone was reported by Bernstein and Swift in 1979 in a patient with PBC.I4The concept of increased opioidergic tone in cholestasis implicates a specific class of substances, endogenous opioids, in its pathogenesis. The presence of naloxonereversible antinociception in a rat model of cholestasis further supports the concept that increased opioidergic neurotransmission contributes to the pathophysiology of this syndrome.'O
Behavioral Studies on the Pruritus of Cholestasis: Use Of Quantitative Methodology The measurement of the concentration of substances that circulate in human plasma and which may rise as a result of cholestasis has not led to the identification of specific substances that are implicated may be associated in the pruritus of cholestasis, even if those substances are associated with pruritus and scratching under experimental conditions. Until recently, clinical trials of therapies for the pruritus of cholestasis have utilized subjective efficacy endpoints. Pruritus is a perception and because it is a perception it cannot be objectively quantitated. The need to apply objective quantitative methodology in studies of the efficacy of therapies for the pruritus of cholestasis has been recognized for years.28,70, 71 The sensation of pruritus or itch elicits the need to scratch.&To objectively evaluate scratching behavior, the authors developed an instrument that allowed for the quantitation of scratching activity independent of body movement.79
Studies of Opiate Antagonist Drugs that Apply Quantitative Methodology The hypothesis that increased opioidergic neurotransmission contributes to the pathophysiology of cholestasis and to the pruritus associated with it was tested in clinical studies, including a double-blind, placebocontrolled trial of the opiate antagonist naloxone in patients with cholestasis and pruritus.8, Naloxone infusions (0.2 Fg/kg/min preceded by an intravenous bolus injection of 0.4 mg of naloxone), in contrast to placebo infusions, were associated with a decrease in the perception of pruritus, as assessed by the visual analogue scale, and a decrease in scratching a~tivity.~ These findings support a role for the endogenous opioid system in the pathogenesis of the pruritus of cholestasis. An important result of this study was that some patients exhibited a circadian rhythm in their scratching behavior, suggesting that the scratching monitoring device recorded a true biological activity (Fig. 2). Administration of naloxone infusions (preceded by bolus injections,
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Hours
Figure 2. Mean hourly scratching activity during 96 hours of quantitation in a patient with pruritus of cholestasis. The continuous solid line indicates the 24-hour rhythm that best fits the observations. (From Bergasa NV, Alling DW, Talbot TL, et al: Naloxone ameliorates the pruritis of cholestasis. Results of a double-blind randomized placebo-controlled trial. Ann lntl Med 123:161-167, 1995; with permission.)
as described above) with dose titration to achieve a subjective decrease in pruritus is a reasonable approach to treat patients with intractable pruritus, a condition that can be considered a medical emergency. Naloxone infusions were administered at doses ranging from 0.2 to 1.26 pg/ kg/min to patients with the pruritus of cholestasis who were awaiting liver transplantation, with reported subjective relief and no deleterious side effe~ts.4~ The preferred mode of administration for naloxone is parenteral because of its low oral bioavailability. Thus, naloxone is impractical for the long term management of patients with the pruritus of chronic cholestasis. Nalmefene is a specific opiate antagonist which is orally bioavailable, more potent than naloxone, and has a more prolonged In, an open label study, nalpharmacological action than n a l ~ x o n e . ~ ~ mefene administration was associated with a significant subjective amelioration of pruritus, as measured by a visual analogue scale of pruritus, and a significant decrease in scratching activity (Figs. 3 and 4).*Nalmefene was administered at doses much lower than in a previous studys1 in an attempt to prevent the opiate withdrawal-like reaction that had been reported to occur when small doses of nalmefene were administered to patients with the pruritus of cholestasis.sl Although some reactions suggestive of an opiate withdrawal-like reaction were observed, their frequency and severity were much less than those previously reported.s1 Oral nalmefene currently is not licensed; however, another potent opiate antagonist that also is orally bioavailable, naltrexone, can be administered orally and has been available for several years. The concern regarding the administration of the drug naltrexone is its potential hepatotoxicity, which appears to be dose related, and its tolerability (E. Anthony Jones, MD, unpublished observations, 1996).63The rationale for its administration, however, would be the same as that for naloxone and nalmefene. Naltrexone at doses of 50 mg per day has been studied in a placebo-controlled study of patients with the pruritus of cholestasis
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baseline
nalmefene
Figure 3. The perception of pruritus as assessed by a visual analogue scale for pruritus before and during nalmefene therapy in a group of patients with cholestatic liver disease. There was a significant decrease in the mean visual analogue score for pruritus on nalmefene when compared to the mean score prior to treatment (baseline). (From Bergasa NV, Alling DW, Talbot TL, et al: Relief from the intractable pruritus of chronic cholestasis associated with oral nalrnefene therapy. Hepatology 14:A154, 1991; with permission.)
without apparent toxicity and with subjective relief of their pruritus as assessed subjectively.88
The Serotonin System in the Pruritus of Cholestasis
The serotonin system appears to be involved in the transmission of nociception (i.e., sensation of pain).69By analogy with the opioid system, it seems possible that the serotonin system may also be involved in the mediation of pruritus. When the serotonin receptor type 3 antagonist ondansetron (8 mg) was administered intravenously to patients with the pruritus of cholestasis, subjective relief of pruritus lasting several hours was In one placebo controlled study, ondansetron, but not placebo injection was also associated with subjective relief of this form of pruritus." In a short term placebo-controlled study intravenously and orally administered ondansetron did not decrease scratching activity in The short duration of this patients with the pruritus of chole~tasis.~~ study may not have allowed the full effects of ondansetron to become apparent, because scratching activity may have become habitual in the patients studied.26,6o Indeed, a prolonged period of administration of
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c
m
2 ~
Figure 4. Mean log,, hourly scratching activity at baseline and during nalmefene therapy in a group of patients with the pruritus of cholestasis. (From Bergasa NV, Alling DW, Talbot TL, et al: Relief from the intractable pruritus of chronic cholestasis associated with oral nalmefene therapy. Hepatology 14:A154, 1991; with permission.)
:
8
1.o
b baseline
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ondansetron (e.g./ several weeks) may be necessary for an effect on scratching activity to become apparent. Increased opioidergic neurotransmission in cholestasis" may alter serotoninergic neurotransmission since these two neurotransmitter systems have neuronal connections in the brain. Experiments in laboratory animals suggest that opioid-induced analgesia can be blocked by ond a n ~ e t r o n Experiments .~~ demonstrating increased serotonergic neurotransmission in animal models of cholestasis, however, have not been reported. CONCLUSION
The pruritus of cholestasis is a difficult clinical problem to manage and requires scientific studies to understand its pathogenesis. The application of quantitative methodology in clinical studies has proven to be an important approach in indentifying a specific neurotransmitter system that appears to be involved in the mediation of this form of pruritus. The use of resins (e.g./ cholestyramine) and the antibiotic rifampicin appears to offer relief of the pruritus of cholestasis in some patients, as
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evaluated by subjective methodology. However, the mechanisms of the ameliorations associated with the administration of these agents have not been determined. The concept that neurotransmitter systems are involved in the mediation of the pruritus of cholestasis is evolving. Recently, data that have emerged from studies of animal models and patients support the hypothesis that increased central opioidergic neurotransmission contributes to the pathophysiology of cholestasis and potentially to the pruritus of cholestasis. The data supporting this hypothesis provide a rationale for the use of opiate antagonist drugs for the treatment of the pruritus of cholestasis, and drugs of this class have been shown to ameliorate this form of pruritus in controlled clinical studies. The factors that lead to alterations in opioidergic neurotransmission in cholestasis are uncertain, but the cholestatic liver may be a source of endogenous opioid agonist peptides in chole~tasis.’~
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